The present invention relates to novel piperazine derivatives, processes for their preparation, pharmaceutical compositions containing the same and to their use in the treatment of CNS and other disorders.
WO 95/06637 discloses a series of piperazine derivatives which are said to possess 5-HT1D receptor antagonist activity. These compounds are alleged to be of use in the treatment of various CNS disorders such as depression. The human 5-HT1D receptor is now known to be encoded by two distinct genes initially designated 5-HT1Dxcex1and 5-HT1Dxcex2and subsequently redesignated as 5-HT1D and 5-HT1B respectively (P. R. Hartig et al, Trends in Pharmacological Science, 1996, 17, 103-105). WO 98/50538 and WO 98/47885 disclose a series of piperazine derivatives that are said to exhibit combined 5-HT1A, 5-HT1B and 5-HT1D receptor antagonist activity. WO 98/27058 discloses a series of carboxamide derivatives that are claimed to be 5-HT6 receptor antagonists.
A structurally novel class of compounds has now been found which also exhibit 5-HT1B receptor activity. In a first aspect, the present invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: 
in which Ra is a group of formula (i) 
wherein P1 is phenyl, naphthyl or heteroaryl;
R1 is halogen, C1-6alkyl, C3-6cycloalkyl, COC1-6alkyl, C1-6alkoxy, hydroxy, hydroxyC1-6alkyl, nitro, CF3, cyano, SR6, SOR6, SO2R6, SO2R6, SO2NR6R7, CO2R6, CONR6R7, OCONR6R7, NR6R7, NR6CO2R7, NR6CONR7R8, CR6xe2x95x90NOR7 where R6, R7 and R8 are independently hydrogen or C1-6alkyl;
a is 0, 1, 2 or 3;
or Ra is a group of formula (ii) 
xe2x80x83wherein
P2 is phenyl, naphthyl, heteroaryl or a 5 to 7 membered heterocyclic ring;
P3 is phenyl, naphthyl or heteroaryl;
A is a bond or oxygen, carbonyl, CH2 or NR4 where R4 is hydrogen or C1-6alkyl;
R2 is as defined above for R1 in formula (i) or R2 is heteroaryl optionally substituted by C1-6alkyl, halogen or COC1-6alkyl or is a 5-7 membered heterocyclic ring optionally substituted by oxo;
R3 is halogen, C1-6alkyl, C3-6cycloalkyl, C1-6alkoxy, COC1-6alkyl, hydroxy, nitro, CF3, cyano, CO2R6, CONR6R7, NR6R7 where R6 and R7 are as defined above;
b and c are independently 0, 1, 2 or 3;
Y is a single bond, CH2, O or NR5 where R5 is hydrogen or C1-6alkyl;
W is xe2x80x94(CR9R10)txe2x80x94 where t is 2, 3 or 4 and R9 and R10 are independently hydrogen or C1-6alkyl or W is a group CHxe2x95x90CH;
Rb is hydrogen, halogen, hydroxy, C1-6alkyl, CF3, COC1-6alkyl, cyano or C1-6alkoxy;
Rc is hydrogen or C1-6alkyl;
Rd and Re are independently C1-4alkyl.
Alkyl groups, whether alone or as part of another group, may be straight chain or branched. The term xe2x80x98halogenxe2x80x99 is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.
Where used herein the term naphthyl is intended, unless otherwise stated, to denote both naphth-1-yl and naphth-2-yl groups.
The term xe2x80x9cheteroarylxe2x80x9d is intended to mean an aromatic or a benzofused aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur. Suitable examples of such aromatic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl. Suitable examples of such benzofused aromatic rings include quinolinyl, isoquinolinyl, indolyl, benzofuryl, benzothienyl, benzimidazolyl, benzoxazolyl and the like.
The term xe2x80x9c5-7 membered heterocyclic ringxe2x80x9d is used herein to mean a non aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur. Suitable examples of such non aromatic rings include piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl.
The heteroaryl and 5-7 membered heterocyclic rings, as described above, may be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom.
Within the Definition of Ra Formula (i)
When P1 is heteroaryl a preferred example is pyridyl. Preferably P1 is phenyl or naphthyl, most preferably phenyl.
When a is other than 0, preferred R1 groups include halogen (particularly fluoro or chloro), C1-6alkyl group (particularly methyl), CF3 and cyano. When a is 2 or 3 the groups R1 can be the same or different.
Preferably a is 1 or 2, most preferably 2.
Within the Definition of Ra Formula (ii)
Preferably A is a bond.
When P3 is heteroaryl preferred examples include quinolinyl and pyrazolyl. P3 is preferably phenyl or naphthyl. A preferred substitution arrangement for such naphthyl groups is 1,4 or 1,5, that is to say, a naphth-1-yl group in which the group A is attached at the 4 or 5 position respectively.
P2 is preferably phenyl, a heteroaryl group such as pyridyl, pyrazinyl, oxadiazolyl or oxazolyl or P2 is a 5-7 membered heterocycle such as piperidinyl.
When b is other than 0, preferred R2 groups include halogen (particularly chloro), C1-6alkyl group (particularly methyl), heteroaryl (particularly oxadiazolyl optionally substituted by C1-6alkyl) or a 5-7 membered heterocyclic ring (particularly 2-oxo pyrrolidinyl). When b is 2 or 3 the groups R2 may be the same or different. Preferably b is 0, 1 or 2.
When c is other than 0, preferred R3 groups are halogen (particularly chloro) and C1-6alkyl group (particularly methyl). When c is 2 or 3 the groups R3 may be the same or different. Preferably c is 0 or 1.
A preferred group of formula (ii) is that in which A is a single bond, P2 is pyridyl (particularly 2-pyridyl) and P3 is naphthyl particularly naphth-1-yl). A further preferred group of formula (ii) is that in which A is a single bond, P2 is pyridyl and P3 is phenyl. Such groups may be optionally substituted by the preferred R2 and R3 groups as described above.
Y is preferably a single bond, CH2 or a NH group.
It will be appreciated that when W is a group xe2x80x94CHxe2x95x90CHxe2x80x94 an indole ring is formed. Within the definition of the group W, the groups R9 and R10 are each preferably hydrogen and t is preferably 2 or 3, most preferably 2.
Rb is preferably hydrogen, C1-6alkoxy group (particularly methoxy) or C1-6alkyl group (particularly methyl).
Rc is preferably hydrogen or methyl.
Preferably both Rd and Re are methyl.
Preferred compounds of this invention are examples E1-E73 (as described below) or a pharmaceutically acceptable salt thereof. Particularly preferred compounds according to this invention are:
cis-1-[(2-chloro-3-trifluoromethylphenyl)acetyl]-6-(3,4,5-trimethylpiperazin-1-yl)indole,
cis-1-[(2-fluoro-3-trifluoromethylphenyl)acetyl]-5-methoxy-6-(3,4,5-trimethylpiperazin-1-yl)indoline,
cis-1-[(2,3dichlorophenyl)acetyl]-6-(3,5-dimethylpiperazin-1-yl)-5-methoxyindoline
cis-6-(3,5-dimethylpiperazin-1-yl)-5-methoxy-1-[4-(2-methyl-6-(2-oxopyrrolidin-1-yl)pyridin-3-yl)benzoyl]indoline,
cis-1-[(3-chloro-2-fluorophenyl)acetyl]-6-(3,5-dimethylpiperazin-1-yl)-5-methoxyindole,
cis-1-[(2-fluoro-3-trifluoromethylphenyl)acetyl]-5-fluoro-6-(3,4,5-trimethylpiperazin-1-yl)indole,
cis-1-[2-chloro-3-(trifluoromethyl)phenyl)aminocarbonyl]-5-methyl-6-(3,4,5-trimethylpiperazin-1-yl)indoline
or a pharmaceutically acceptable salts thereof.
The compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci., 1977, 66, 1-19, such as acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.
The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be hydrated or solvated. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.
Compounds of the invention can be prepared using procedures known in the art. In a further aspect the present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof which comprises either:
(a) where Y is NH, coupling a compound of formula (II):
Raxe2x80x94Nxe2x80x94(Cxe2x95x90O)xe2x80x83xe2x80x83(II)
in which Ra is as defined in formula (I) with a compound of formula (III): 
in which W, Rb, Rc, Rd and Re are as defined in formula (I); or
(b) where Y is NR5, reacting a compound of formula (IV)
Raxe2x80x94NR5Hxe2x80x83xe2x80x83(IV)
in which Ra and R5 are as defined in formula (I) with a compound of formula (III) as defined above together with an appropriate urea forming agent; or
(c) where Y is a single bond, CH2 or O, reacting a compound of formula (V)
Raxe2x80x94Yxe2x80x94(Cxe2x95x90O)xe2x80x94Lxe2x80x83xe2x80x83(V)
in which Ra is as defined in formula (I) and L is an appropriate leaving group, with a compound of formula (III) as defined above; and optionally thereafter for either process (a), (b) or (c):
removing any protecting groups,
converting a compound of formula (I) into another compound of formula (I),
forming a pharmaceutically acceptable salt.
The reaction in process (a) is conveniently effected in an organic solvent such as dichloromethane.
In process (b) the urea forming agent can be carbonyl diimidazole, triphosgene or phosgene, and carried out in an inert organic solvent such as dimethylformamide, tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine.
In process (c) the leaving group L may be a halogen e.g. chloro group and the reaction may be carried out in an inert organic solvent such as tetrahydrofuran or dichloromethane at ambient or elevated temperature in the presence of a base such as triethylamine or pyridine. Alternatively L may be an O-benzotriazole group, prepared from hydroxybenzotriazole and a carbodiimide, and the reaction may be carried out in an inert organic solvent such as tetrahydrofuran, dichloromethane or dimethylformamide at ambient or elevated temperature.
Compounds of formula (I) can be converted into further compounds of formula (I) using standard techniques. The following examples are given by way of illustration of this point rather than limitation. For compounds of formula (I) wherein Rc is hydrogen, it is possible to introduce a C1-6alkyl group by conventional alkylation using 1 molar equivalent of a C1-6alkyl halide and 1 molar equivalent of a suitable base in an inert solvent. For compounds of formula (I) wherein W is a group xe2x80x94CH2CH2xe2x80x94, it is possible to convert this to a group wherein W is xe2x80x94CHxe2x95x90CHxe2x80x94 with an oxidising agent such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in an inert solvent such as dichloromethane or toluene.
Intermediate compounds of formula (II), (III), (IV) and (V) are either commercially available or can be prepared using methods described herein, by methods known to those skilled in the art or by analogous methods thereto. For example, where intermediates of formula (V) are derived from phenylacetic acids, the latter may be prepared from the corresponding benzoic acids by standard homologation methods involving reduction to the benzyl alcohol, followed by conversion to the benzyl bromide, displacement with an inorganic cyanide to afford the benzonitrile, followed by acid or base hydrolysis.
It will be appreciated to those skilled in the art that it may be necessary to protect certain reactive substituents during some of the above procedures. Standard protection and deprotection techniques can be used. For example, primary amines can be protected as phthalimide, benzyl, benzyloxycarbonyl or trityl derivatives. Carboxylic acid groups can be protected as esters. Aldehyde or ketone groups can be protected as acetals, ketals, thioacetals or thioketals. Deprotection of such groups is achieved using conventional procedures well known in the art.
Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.
The involvement of serotonin (5-hydroxytryptamine; 5-HT) receptors in a number of pharmacological effects has been reviewed by R. A. Glennon in xe2x80x9cSerotonin Receptors: Clinical Implicationsxe2x80x9d, Neuroscience and Behavioural Reviews, 1990, 14, 35 and by L. O. Wilkinson and C. T. Dourish in xe2x80x9cSerotonin Receptor Subtypes: Basic and Clinical Aspectsxe2x80x9d S. Peroutka Ed., John Wiley and Sons, New York, 1991 p. 147.
Serotonin receptors have been implicated in pharmacological effects such as mood disorders including depression, seasonal affective disorder and dysthymia, anxiety disorders, including generalized anxiety, panic disorder, agoraphobia, social phobia, obsessive compulsive disorder and post-traumatic stress disorder, memory disorders, including dementia, amnesic disorders and age-associated memory impairment; disorders of eating behaviours, including anorexia nervosa and bulimia nervosa, sleep disorders (including disturbances of circadian rhythm), motor disorders such as Parkinson""s disease, dementia in Parkinson""s disease, neuroleptic-induced Parkinsonism and tardive dyskinesias, pain disorders as well as other psychiatric disorders such as schizophrenia and psychosis. Serotonin receptor ligands have been shown to be of use in the treatment of emesis and nausea and may also be of use in endocrine disorders such as hyperlactinaemia, vasospasm (particularly in the cerebral vasculature), cerebellar ataxia and hypertension, as well as disorders of the gastrointestinal tract where changes in motility and secretion are involved. They may also be of use in the treatment of pre-menstrual tension, sexual dysfunction and hypothermia.
Ligands with high affinity for the 5-HT1 receptors are well recognised as having therapeutic utility for the treatment of the above conditions. It has been suggested that a selective 5-HT1B receptor antagonist should act as a fast onset antidepressant (P. Blier Trends Pharmacol. Sci. 1994, 15, 220).
The present invention also provides for a compound of formula (I) or a pharmaceutically acceptable salt for use in the treatment of the aforementioned disorders. In particular, the invention provides for a compound of formula (I) or a pharmaceutically acceptable salt for use in the treatment or prophylaxis of depression.
In a further aspect the invention provides a method of treating disorders where an antagonist of the 5-HT1B receptor is beneficial, particularly the aforementioned disorders, which comprises administering a safe and therapeutically effective amount of compound of formula (I) or a pharmaceutically acceptable salt to a patient in need thereof.
In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of disorders in which an antagonist of the 5-HT1B receptor is beneficial, particularly the aforementioned disorders, more particularly depression.
The affinities of the compounds of this invention for the 5-HT1B receptor can be determined by the following radioligand binding assay. CHO cells expressing 5-HT1B receptors (4xc3x97107 cells/ml) are homogenised in Tris buffer Mg2+ and stored in 1.0 ml aliquots. 0.4 ml of a cell suspension is incubated with [3H]-5-HT (4 nM) in Tris Mg HCl buffer (pH 7.7) and test drug, at 37xc2x0 C. for 45 minutes. Each test drug is tested at 10 concentrations (0.01 mM to 0.3 nM final concentration), with non-specific binding defined using 0.01 mM 5-HT. The total assay volume is 0.5 ml. Incubation is stopped by rapid filtration using a Tomtec Harvester (filters pre-washed in 0.3% polyethylenimine) and radioactivity measured by Topcount scintillation counting. pKi values are calculated from the IC50 generated by an iterative least squares curve fitting programme.
All examples tested in accordance with this radioligand binding assay were found to have a pKi greater than 7.3 at 5-HT1B receptors with many demonstrating a pKi in the higher range of 8.0-9.2.
The selectivity of the compounds of this invention for 5-HT1B receptors can be determined using binding assay methods which are well known to those skilled in the art. All examples tested were found to have a greater than a 10-fold selectivity over 5-HT1D receptors and a greater than 50-fold selectivity over other binding sites within the CNS, in particular, other 5-HT receptor sub-types and dopaminergic receptors. Many examples were found to have a greater than a 30fold selectivity over 5-HT1D receptors and a greater than 80-fold selectivity over other binding sites.
The intrinsic activity of the compounds of this invention can be determined according to the following procedure. CHO cell membranes stably expressing human 5-HT1B receptors are homogenised in HEPES/EDTA buffer and stored in 1 ml aliquots, and [35S]GTPxcex3S binding studies are carried out essentially as described by Lazareno et al., (Life Sci., 1993, 52, 449) with some minor modifications. Membranes from 106 cells are pre-incubated at 30xc2x0 C. for 30 minutes in 20 mM HEPES buffer (pH 7.4) in the presence of MgCl2 (3 mM), NaCl (100 mM), GDP (10 xcexcM) and ascorbate (0.2 mM), with or without compounds. The reaction is started by the addition of 50 xcexcl of [35S]GTPxcex3S (100 pm, assay concentration) followed by a further 30 minutes incubation at 30xc2x0 C. Non-specific binding was determined using non-radiolabelled GTPxcex3S (20 xcexcM) added prior to the membranes. The reaction is terminated by rapid filtration through Whatman GF/B grade filters followed by 5xc3x971 ml washes with ice cold HEPES (20 mM)/MgCl2 (3 mM) buffer. Radioactivity is measured using liquid scintillation spectrometry. This procedure is hereafter referred to as the [35S]GTPxcex3S functional assay.
It has been found, using the [35S]GTPxcex3S functional assay, that certain compounds of formula (I) show varying levels of intrinsic efficacy, which is defined by a scale in which the value 1.0 defines the maximum response elicited by the agonist 5-HT, 0.0 defines antagonism and a negative value indicates inverse agonism. The difficulties in describing intrinsic activity of drugs acting at G protein coupled receptors is recognised in the art (Hoyer and Boddeke, Trends in Pharmacological Sciences, July 1993, [Vol. 14], page 270-275). We believe that however these ligands are classified according to this functional assay, the compounds of this invention will be useful antidepressants in vivo. It is believed that the preferred compounds of this invention will display 5-HT1B antagonist activity in vivo and that such compounds will have a rapid onset of action. A rapid onset of action is particularly advantageous for antidepressant compounds: by xe2x80x98rapid onset of actionxe2x80x99 we mean that a therapeutic response is seen within 7 days from first administration of the compound, as opposed to a period of about 21 days or more which is typical of SSRI""s, tricyclic antidepressants and buspirone.
Compounds of formula (I) which have an intrinsic activity of 0.5 or less in the in vitro [35S]GTPxcex3S functional assay are preferred, as these compounds are more likely to be full antagonists in vivo. Particularly preferred compounds of this invention have an intrinsic activity in the range 0.0-0.3 or are inverse agonists in this functional assay.
It has been found that the compounds of this invention have a particularly advantageous profile in that they demonstrate high affinity and selectivity for the 5-HT1B receptor together with low intrinsic activity in the [35S]GTPxcex3S functional assay.
It will be appreciated by those skilled in the art that the compounds according to the invention may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents.
In order to use the compounds of formula (I) in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.
The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three times a day. Such therapy may extend for a number of weeks or months.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.